Prior art implants and fillers for use in biological applications generally do not allow thermally reversible removal or modification of the substance used. For example, the use of silicone implants and polymeric implants do not allow easy modification of shape, volume or placement in a reversible way, once the implant is in place.
In reconstructive and cosmetic surgery and other cosmetic procedures, the success or failure of the procedure depends in part on the satisfaction of the patient with the appearance of their altered physical attribute. There are very few methods available, short of a subsequent surgery or repeat procedures, to correct errors or affect changes to a cosmetic alteration.
With an aging population and a concurrent emphasis on youthful appearance, a number of methods have arisen for reducing facial lines and wrinkles. One such method involves injection of a toxin below the skin to cause a localized immune reaction that smoothes out wrinkles. One problem with this method is the potential or perceived danger to the patient due to unexpected reactions to the toxin. Other methods involve injection of natural materials (e.g., collagen and hyaluronic acid) under the wrinkle to raise the skin. One problem with these implants is the potential or perceived danger that these materials may be immunogenic, be allergenic or carry animal-borne diseases (e.g., mad cow disease or its human equivalent—Creutzfeldt-Jacob Disease). In addition, these implants begin to degrade upon implantation, making it difficult or impossible to remove them, if necessary. In some cases, small, non-degradable beads (e.g., polymethymethacrylate) are suspended in wrinkle fillers to give them a longer-lasting effect. These small beads become surrounded by fibrous tissue as part of the normal foreign body reaction to implants, which prolongs their effect, but makes them impossible to remove, if desired.
Current methods of birth control are either irreversible, or only reversible through lengthy surgical procedures (for example, a reverse vasectomy). Other methods, such as “the pill” use pharmaceutical means to cause a temporarily infertile state. Subject compliance is necessary for the success of such methods. There is a need for reversible long-term options for birth control for both men and women.
Block and graft copolymers are used for a variety of physiological and industrial applications. The solubility of a copolymer in a particular solvent depends inter alia on the characteristics of the monomeric components incorporated into the copolymer.
Polymers capable of gelation induced by environment changes are known. Solvent-induced gelation has also been exploited as a mechanism for producing in situ gelable materials. The solvent-induced gelation concept employs a polymer that is soluble in a non-aqueous solvent, but insoluble in water. When a non-aqueous solution of such a polymer is injected into an aqueous environment, the non-aqueous solvent is exchanged for water and the polymer precipitates, forming a solid mass in situ. Solvent-induced gelation systems have the disadvantage that the initial fluid form of the polymer is formed in a solvent other than the solvent in which the gel eventually forms. U.S. Pat. No. 5,744,153 (Apr. 28, 1998) and No. 5,759,563 (Jun. 2, 1998), both to Yewey et al., describe a composition for in situ formation of a controlled drug release implant based on the solvent-induced gelation concept.
A series of patents to Dunn et al. also describe a solvent-induced gel composition (U.S. Pat. No. 5,739,176 issued Apr. 14, 1998; U.S. Pat. No. 5,733,950 issued Mar. 31, 1998; U.S. Pat. No. 5,340,849 issued Aug. 23, 1994; U.S. Pat. Nos. 5,278,201 and 5,278,204 both issued Jan. 11, 1994; and U.S. Pat. No. 4,938,763 issued Jul. 3, 1990). The composition includes a water-insoluble polymer and a drug solubilized in an organic solvent carrier. When the composition is injected into a physiological (aqueous) environment, such as a human subject, the polymer precipitates to form a solid mass. Solvent-induced gel compositions have the disadvantage that an organic solvent is injected into a subject merely to carry the polymer and drug in a liquid form. Thus, the organic solvent must subsequently be metabolized or cleared by the body.
Self-assembling hydrogels have been receiving increasing attention in the last few years, both for their intrinsic scientific interest, and for their potential clinical and non-clinical applications. A number of elegant mechanisms for self-assembling hydrogels have been proposed. Nagahara et al. showed that gels can be formed by complexation between complementary oligonucleotides grafted onto hydrophilic polymers (Polymer Gels and Networks, 4:(2) 111–127, 1996). Miyata et al. prepared antigen sensitive hydrogels based on antigen-antibody binding (Miyata et al., Macromolecules, 32: (6) 2082–2084, 1999; Miyata, Nature, 399: (6738) 766–769, 1999). Petka et al. illustrated a gelation mechanism using triblock copolymers containing a central hydrophilic core and terminal leucine zipper peptide domains (Science, 281: (5375) 389–392, 1998). The terminal domains form coil-coil dimers or higher order aggregates to provide crosslinking when cooled from above its pH-dependent melting point. Thermoreversibility was demonstrated with some hysteresis due to the slow kinetics of coil-coil interactions.
Triblock copolymers having a central hydrophobic poly(propylene oxide) (PPO) segment and hydrophilic poly(ethylene oxide) (PEO) segments attached at each end are commercially available. The aqueous solution of these triblock copolymers (PEO-PPO-PEO) have a fluid consistency at room temperature, and turn into weak gels when warmed to body temperature by forming oil-in-water micelles in aqueous solution. The gelation of the polymer is believed to occur via the aggregation of the micelles (Cabana, et al., J. Coll. Int. Sci., 190(1997) 307).
A group led by S. W. Kim have reported the development of thermosensitive biodegradable hydrogels (Jeong et al., J. Controlled Release, 62 (1999) 109–114; Jeong et al., Macromolecules, 32: (21) 7064–7069, 1999; Jeong et al., Nature, 388 (1997) 860–862). These hydrogels are block copolymers of PEO and poly(L-lactic acid) (PLLA) in either a di-block architecture PEO-PLLA, or a tri-block architecture PEO-PLLA-PEO. They also report triblock copolymers of poly(ethylene oxide) and poly(lactide-co-glycolide) (PLGA) having the architecture PEO-PLGA-PEO. Aqueous solutions of these polymers were reported to undergo temperature-sensitive phase transitions between fluid solution and gel phases. In aqueous solution, these polymers form micelles composed of hydrophobic cores (either PLGA or PLLA) and hydrophilic surfaces (PEO). Gelation is believed to be due to the aggregation of micelles driven by hydrophobic interactions. This group has also discussed the synthesis of PEO copolymers in multi-armed star shaped architectures having polycaprolactone (PCL) or PLLA chains attached to the PEO arms.
Another class of in situ gelable materials is based on polymers made from proteins, or “protein polymers”. Cappello, et al. (J Controlled Release 53 (1998) 105–117) reported gelforming block copolymers based on repeating amino acid sequences from silk and elastin proteins. When heated to body temperature, the proteins self-assemble via a hydrogen bond mediated chain crystallization mechanism to form an irreversible gel. The gelation occurs over a relatively long time period of more than 25 minutes.
Although a variety of gelling or precipitatable polyethylene glycol/poly(N-isopropylacrylamide) copolymers have been synthesized, none was designed and synthesized with in situ gelation applications in mind. See, for example Yoshioka et al., J. M. S Pure Appl. Chem., A31: (1) 109–112, 1994; Yoshioka, J. M. S. Pure Appl. Chem., A31: (1) 113–120, 1994; Yoshioka, J. M. S Pure Appl. Chem., A31: (1) 121–125, 1994; Kaneko, Macromolecules, 31: 6099–6105, 1998; Topp, et al., Macromolecules, 30: 8518–8520, 1997; and Virtanen, Macromolecules, 33: 336–341, 2000.
Topp et al. disclose block copolymers of PEG and PNIPAAm having the structure of either PNIPAAm-PEG or PNIPAAm-PEG-PNIPAAM which form spherical micelles in aqueous solution (Macromolecules, 30: 8518–8520, 1997). The block copolymers were synthesized by the Ce+4 initiated attachment of NIPAAm monomers onto the hydroxyl terminals of PEG chains. It was shown that as PNIPAAm segments grew in length during synthesis, micelles having a PNIPAAm core and PEG corona were formed, and the polymerization of PNIPAAm chains continued in the core of the micelles. The copolymers formed by Topp et al. are of a form appropriate for use in a surfactant composition for drug loaded micelles. However, micelles are isolated entities having no load bearing characteristics, do not form gels, and the formation of micelles is associated with a dilute solution state.
The block copolymers formed by Topp et al. consisted of compositions with PNIPAAm to PEG mass ratios (Mn,PNIPAAm/Mn,PEG) ranging from about 0.14 to 0.48, and they found that block copolymers with a Mn,PNIPAAm/Mn,PEG ratio exceeding ⅓ show aggregation in water at temperatures below the lower critical solution temperature (LCST) at which a solubility change occurs, and thus are less useful for micelle formation than copolymers with ratios less than ⅓.
There is a need for a gelable polymer that is responsive to environmental changes other than solvent exchange. Further, there is a need for a gelable polymer composition capable of reversibly forming a strong gel.